rac-N-(4-Ethoxyphenyl)-3-hydroxybutanamide

The crystal structure of bucetin, an analgesic and antipyric similar to phenacetin, is presented.

In the title compound, racemic bucetin [systematic name: N-(4-ethoxyphenyl)-3hydroxybutanamide], C 12 H 17 NO 3 , the molecule is in an extended conformation as illustrated by the C-O-C-C torsion angle [170.14 (15) ] in the ethoxy group and the subsequent C-N-C-C [À177. 24 (16) ], N-C-C-C [170.08 (15) ] and C-C-C-C [171.41 (15) ] torsion angles in the butanamide chain. In the crystal, the O-H group donates an intermolecular O-HÁ Á ÁO hydrogen bond to the amide carbonyl oxygen atom and also accepts an intermolecular N-HÁ Á ÁO hydrogen bond from an adjacent N-H group. The former forms 12-membered dimeric rings about inversion centers, and the latter form chains in the [001] direction. The overall hydrogen-bonded network is twodimensional, with no propagation in the [100] direction.

Structure description
N-(4-Ethoxyphenyl)-3-hydrobutanamide, popularly known as bucetin, is an analgesic and antipyric that is similar in structure to phenacetin [N-(4-ethoxyphenyl)acetamide]. Once thought to be a better substitute for phenacetin (Ehrhart et al., 1965;Ehrhart & Ott, 1958), bucetin was introduced into the markets in Germany but was soon withdrawn from use because of renal toxicity and risk of carcinogenesis (Fung et al., 2001;Togei et al., 1987). The renal toxicity of bucetin, renal papillary necrosis, is similar in nature to that induced by phenacetin but is somewhat less pronounced, presumably due to differences in the rates of deacylation by microsomal enzymes leading to the formation of 4-ethoxyaniline (Nohmi et al., 1984). Thus, the renal papillary necrosis by phenacetin and bucetin appears to be a manifestation of the formation of 4-ethoxyaniline and the subsequent inhibitory action(s) of this putative metabolite (or its hydroxylated and/or autooxidation products, N-(4-ethoxyphenyl)hydroxylamine and 1-ethoxy-4-nitroso-data reports benzene) on PGE2 synthesis and a possible reduction of COX-2 expression (Camus et al., 1982;Goodin et al., 2002;Kankuri et al., 2003;Wirth et al., 1982).
Previous studies from our laboratory and elsewhere have shown that celluar oxidants, such as peroxynitrite/peroxynitrous acid and hypochlorite/hypochlorous acid, can constitute an important pathway for non-enzymatic biotransformation of N-(4-hydroxyphenyl)acetamide (Bedner & MacCrehan, 2006;Uppu & Martin, 2004;Whiteman et al., 1996), apocynin (Gernapudi et al., 2009), clozapine (Frimat et al., 1997;Uppu et al., 2005), and certain other xenobiotics (Babu et al., 2012;Ju & Uetrecht, 1998;Rattay & Benndorf, 2021). We believe that the above referenced oxidants may also be involved in the biotransformation of bucetin, leading to the formation of hydroxylated, chlorinated, and nitrated products and thus contribute to the toxicity. To address this and to better understand the mechanisms of toxicity of bucetin and phenacetin and its congeners, we determined the crystal structure of racemic bucetin.
As shown in Fig. 2, the OH group donates an intermolecular hydrogen bond to the amide carbonyl oxygen atom and accepts an intermolecular hydrogen bond from an adjacent N-H group. The donor-acceptor separations for these hydrogen bonds are 2.7268 (17) Å for O-HÁ Á ÁO(Àx + 1, Ày + 1, Àz + 2) and 2.8611 (19) Å for N-HÁ Á ÁO(x, Ày + 1 2 , z À 1 2 ). The former thus forms 12-membered dimeric rings about inversion centers, and the latter form chains in the [001] direction. The overall hydrogen-bonded network is twodimensional, with no propagation in the [100] direction. The packing in the unit cell is shown in Fig. 3 and includes also C-HÁ Á ÁO interactions (Table 1).
Given the current understanding that de-acylation constitutes an important step in the expression of renal toxicity (Kankuri et al., 2003;Nohmi et al., 1984;Taxak et al., 2013), and the fact that the acyl group in bucetin (3-hydroxybutyryl) is much larger in size compared to the acetyl group in phenacetin and its congeners and has a chiral center, the information on the crystal structure of bucetin presented here may help in the development of analgesics with little or no renal toxicity.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2.

Funding information
The authors acknowledge the support from the National Institutes of Health (